Treatment response of colorectal cancer liver metastases to neoadjuvant or conversion therapy: a prospective multicentre follow-up study using MRI, diffusion-weighted imaging and 1H-MR spectroscopy compared with histology (subgroup in the RAXO trial)

A Uutela, A Ovissi, A Hakkarainen, A Ristimäki, N Lundbom, R Kallio, L M Soveri, T Salminen, A Ålgars, P Halonen, R Ristamäki, A Nordin, R Blanco Sequeiros, I Rinta-Kiikka, E Lantto, J Virtanen, E Pääkkö, E Liukkonen, J Saunavaara, P Ryymin, E Lammentausta, P Osterlund, H Isoniemi, RAXO Study Group, Heikki Mäkisalo, Riikka Huuhtanen, Juhani Kosunen, Sirpa Leppä, Petri Bono, Johanna Mattson, Emerik Österlund, Heidi Penttinen, Siru Mäkelä, Olli Carpén, Marjut Timonen, Kaisa Lehtomäki, Veera Salminen, Niina Paunu, Martine Vornanen, Nieminen Lasse, Eetu Heervä, Eija Korkeila, Eija Sutinen, Maija Lavonius, Jari Sundström, Markus Mäkinen, Tuija Poussa, A Uutela, A Ovissi, A Hakkarainen, A Ristimäki, N Lundbom, R Kallio, L M Soveri, T Salminen, A Ålgars, P Halonen, R Ristamäki, A Nordin, R Blanco Sequeiros, I Rinta-Kiikka, E Lantto, J Virtanen, E Pääkkö, E Liukkonen, J Saunavaara, P Ryymin, E Lammentausta, P Osterlund, H Isoniemi, RAXO Study Group, Heikki Mäkisalo, Riikka Huuhtanen, Juhani Kosunen, Sirpa Leppä, Petri Bono, Johanna Mattson, Emerik Österlund, Heidi Penttinen, Siru Mäkelä, Olli Carpén, Marjut Timonen, Kaisa Lehtomäki, Veera Salminen, Niina Paunu, Martine Vornanen, Nieminen Lasse, Eetu Heervä, Eija Korkeila, Eija Sutinen, Maija Lavonius, Jari Sundström, Markus Mäkinen, Tuija Poussa

Abstract

Background: Colorectal cancer liver metastases respond to chemotherapy and targeted agents not only by shrinking, but also by morphologic and metabolic changes. The aim of this study was to evaluate the value of advanced magnetic resonance imaging (MRI) methods in predicting treatment response and survival.

Patients and methods: We investigated contrast-enhanced MRI, apparent diffusion coefficient (ADC) in diffusion-weighted imaging and 1H-magnetic resonance spectroscopy (1H-MRS) in detecting early morphologic and metabolic changes in borderline or resectable liver metastases, as a response to first-line neoadjuvant or conversion therapy in a prospective substudy of the RAXO trial (NCT01531621, EudraCT2011-003158-24). MRI findings were compared with histology of resected liver metastases and Kaplan-Meier estimates of overall survival (OS).

Results: In 2012-2018, 52 patients at four Finnish university hospitals were recruited. Forty-seven patients received neoadjuvant or conversion chemotherapy and 40 liver resections were carried out. Low ADC values (below median) of the representative liver metastases, at baseline and after systemic therapy, were associated with partial response according to RECIST criteria, but not with morphologic MRI changes or histology. Decreasing ADC values following systemic therapy were associated with improved OS compared to unchanged or increasing ADC, both in the liver resected subgroup (5-year OS rate 100% and 34%, respectively, P = 0.022) and systemic therapy subgroup (5-year OS rate 62% and 23%, P = 0.049). 1H-MRS revealed steatohepatosis induced by systemic therapy.

Conclusions: Low ADC values at baseline or during systemic therapy were associated with treatment response by RECIST but not with histology, morphologic or detectable metabolic changes. A decreasing ADC during systemic therapy is associated with improved OS both in all patients receiving systemic therapy and in the resected subgroup.

Keywords: colorectal cancer; diffusion-weighted imaging; liver metastasis; liver surgery; magnetic resonance spectroscopy; neoadjuvant chemotherapy.

Conflict of interest statement

Disclosure AU, AIH, AO, AR, NL, RK, L-MS, TKS, PMH, RHR, AN, RBS, IR-K, EL, JV, EP, PO, AÅ, EL, JS, PR, EL and HMI have received travel grants and/or honoraria from the following pharmaceutical companies: Amgen, Bayer, BMS, Celgene, Erytech Pharma, Janssen-Cilag, Lilly, Merck, MSD, Nordic Drugs, Roche, Sanofi, Servier/Shire, Sobi, Pierre Fabre and Varian.

Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.

Figures

Figure 1
Figure 1
Contrast-enhanced magnetic resonance imaging (MRI) and diffusion-weighted imaging. A gadolinium-enhanced T1 volumetric interpolated breath-hold examination (VIBE) MRI of a liver metastasis before (A) and after (B) chemotherapy. The corresponding apparent diffusion coefficient (ADC) maps calculated from diffusion-weighted images (DWI) of the same tumour before (C) and after systemic therapy (D). Red area and arrow: whole tumour area. Yellow area and arrow: the postulated active tumour area (ADC periphery, the C-formed rim in image C).
Figure 2
Figure 2
Tumour vitality (TV), tumour regression grade (TRG) and modified tumour regression grade (mTRG) after neoadjuvant or conversion therapy. (A) No vital tumour cells, fibrosis and infarct-like necrosis, TV 0%, TRG1, mTRG1. (B) A small area of vital tumour cells surrounded by large areas of relatively clean (infarct-like) necrosis, TV 10%, TRG2, mTRG2. (C) Larger areas of vital tumour cells bordered by vital stroma and areas of ‘dirty’ (usual) necrosis, with infarct-like necrosis elsewhere in the slide (not shown), TV 30%, TRG3, mTRG3. (D) Mostly vital tumour, with little fibrosis and necrosis, TV 70%, TRG4, mTRG4.
Figure 3
Figure 3
Overall survival in patients whose liver metastases show a reduction versus increase or no change in the ADC after chemotherapy. (A) Resected patients. (B) All patients treated with neoadjuvant or conversion therapy. ADC, apparent diffusion coefficient; CI, confidence interval; HR, hazard ratio; mCRC, metastatic colorectal cancer.

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Source: PubMed

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